Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-25
1998-06-02
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
435122, C07D21190, C12P 1712
Patent
active
057602387
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/01606 filed Aug. 11, 1995.
TECHNICAL FIELD
The present invention relates to intermediates for preparing optical active 1,4-dihydropyridine derivatives useful as preventive and therapeutic agents for ischemic heart diseases and hypertension. More particularly, the present invention relates to novel 1,4-dihydropyridine derivatives represented by the general formula (I) below ##STR2## (wherein the symbols have the same meanings as defined below) and salts thereof, which are substrates for preparing optical active 1,4-dihydropyridine derivatives by biochemical reactions by using microorganisms and enzymes as well as intermediates of the substrates, and to novel optical active 1,4-dihydropyridine derivatives represented by the general formula (II) ##STR3## (wherein the symbols have the same meanings as defined below) and salts thereof.
BACKGROUND ART
Those 1,4-dihydropyridine compounds having two different carboxylic acid ester groups at the 3- and 5-positions, respectively, of the dihydropyridine ring have an asymmetric carbon atom at the 4-position of the dihydropyridine ring and, hence, provide two kinds of optical isomers. Recent research on the biological effects of these compounds has reported that there are differences between the optical isomers in pharmacological Chem., Vol. 29, 2504 (1986)!.
When the compounds having an asymmetric carbon atom are used as a drug, the idea of administering only one of the isomers that is more preferrable as a drug is becoming generally accepted in order not to give an unnecessary load to the living organism. From this viewpoint, investigation has been made for various methods for preparing optical active 1,4-dihydropyridine derivatives.
Generally known methods for synthesizing optical acitve 1,4-dihydropyridine derivatives include the method using (4R)-1,4-dihydropyridinecarboxylic acid monoester as an intermediate, into which a desired ester radical is
As the method for preparing the optical active intermediates, (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid monoesters, there are known 3465 (1991)!.
Among these methods, the enzymatic methods are excellent manufacturing methods since they asymmetrically hydrolyze prochiral 1,4-dihydropyridine-3,5-dicarboxylic acid diesters so that the other of the isomers, that is unusable and wasted in the chemical method, does not have to be wasted.
However, the enzymatic methods require that the reaction should proceed in an aqueous medium due to their nature. Therefore, the conventional methods, in which highly hydrophobic 1,4-dihydropyridine-3,5-dicarboxylic acid diester is used as a substrate, have failed to proceed the reaction at increased substrate concentrations in spite of use of an auxiliary solvent (acetone, methanol, dimethyl sulfoxide, diemthylformamide and so on) so that only a limited reaction efficiency has been obtained.
Accordingly, there has been a keen demand for the development of an efficient method for preparing an optical active isomer, i.e., (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid monoester, using a substrate which has high polarity and is water-soluble.
DISCLOSURE OF THE INVENTION
As a result of intensive investigation with a view to solving the above-described problems, the present inventors have discovered highly water-soluble substrates suitable for preparing (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivatives by using microorganisms or enzymes, and thus completed the present invention.
Therefore, the present invention provides 1,4-dihydropyridine derivatives described below.
1) 1,4-dihydropyridine derivatives represented by the general formula (I) ##STR4## (wherein X and Y independently represent a hydrogen atom, a nitro group, a nitrile group or a halogen atom, and n is an integer of 1 to 3) or salts thereof.
2) Optical active 1,4-dihydropyridine derivatives represented by the general formula (II) ##STR5## (wherein X, Y and n have the same meanings as defined above) or salts thereof.
3) A method for preparing an optical active 1,4-di
REFERENCES:
patent: 5635395 (1997-06-01), Isshiki et al.
Holdgrun et al., "A Chemoenzymatic Synthesis of Optically-Active Dihydropyridines" Tetrahedron Letters, vol. 32, No. 29, pp. 3465-3468 (1991).
Ebiike et al., "Acyloxymethyl as an Activating Group in Lipase-Catalyzed Enantioselective Hydrolysis . . . " Tetrahedron Letters, vol. 32, No. 41 pp. 5805-5808.
Ashimori et al., "Synthesis and Pharmacological Effects of Optically Active . . . " Chem. Pharm. Bull., vol. 39, No. 1, pp. 108-111 (1991).
Ashimori et al., "Novel 1,4-Dihydropyridine Calcium Antagonists . . . " Chem. Pharm. Bull., vol. 39, No. 1, pp. 91-99 (1991).
Tamazawa et al., "Stereoselectivity of a Potent Calcium Antagonist . . . " J. Med. Chem., vol. 29, No. 12, pp. 2504-2511 (1986).
Shibanuma et al., "Synthesis of Optically Active . . . " Chem. Pharm. Bull., vol. 28, No. 9, pp. 2809-2812 (1980).
Dobashi Kazuyuki
Isshiki Kunio
Matsumoto Naoki
Nakashima Takashi
Tsuruta Takurou
Dentz Bernard
Mason, Jr. Joseph C.
Mercian Corporation
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